A Pediatric Case of Fusobacterium necrophorum Mastoiditis and Meningitis Case Report in a Healthy Child and Review of the Literature

In infants and children, bacterial meningitis caused by anaerobic bacteria is rare. However, a serious infection with the anaerobe Fusobacterium necrophorum can occur in previously healthy children with a peak incidence in preschool children and in adolescents. As the clinical presentation can be very similar to meningitis caused by aerobic bacteria, one should consider Fusobacterium necrophorum as the causative agent when preceded by or associated with otitis media with purulent otorrhea or mastoiditis, in combination with minimal or no improvement on empiric antibiotic treatment. As this pathogen can be difficult to culture, anaerobic cultures should be obtained. Prompt treatment with a third-generation cephalosporin and metronidazole should be initiated once suspected or confirmed. Surgical source control is often necessary, but even with adequate and prompt treatment, the morbidity and mortality in children with a Fusobacterium necrophorum meningitis remains high. In this report, we describe a case of Fusobacterium necrophorum meningitis in a previously healthy child and review the available literature.


Introduction
In infants and children, a relatively small group of aerobic pathogens is responsible for most cases of bacterial meningitis.Tey vary by age, with Streptococcus agalactiae, Escherichia coli, and Listeria monocytogenes common in infants, while Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus infuenza type B are most accountable for in children [1].In contrast, bacterial meningitis caused by anaerobic bacteria in infants and children is rare, and the exact incidence is unknown.Different anaerobic bacteria have been reported, most frequently Bacteroides spp.(fragilis), Clostridium spp.(perfringens), and occasionally Fusobacterium spp.(aquatile, gonidiaformans, and necrophorum) [2][3][4][5].In this report, we describe a case of a Fusobacterium necrophorum (F.necrophorum) meningitis in a previously healthy child and also review the available literature.

Case Report
A 3-year-old girl of Iranian descent, born in Belgium, with no signifcant medical history and immunized with the recommended vaccines, consulted a pediatrician because of left ear pain and fever for three days.Physical examination revealed a left acute otitis media, and amoxicillin was initiated.One week later, on day 10 of her illness, she presented at the emergency department because of persistent fever with anorexia, weight loss and night sweats.Physical examination revealed an erythematous nonbulging tympanic membrane on the left side without clinical signs of meningitis.Infammatory parameters were slightly elevated with a C-reactive protein (CRP) of 40 mg/L (normal value: <3 mg/L).With these fndings, an expectative management was set with a follow-up appointment in two days.Because of persistent fever, the girl was admitted for further diagnostic tests on day 12. Blood investigations now revealed a sedimentation rate of 57 mm/hour (normal value: <13 mm/hour), a white blood cell count of 14.7 × 10 9 /L (normal value: 4-12 × 10 9 /L), and a CRP of 22 mg/L.A nasopharyngeal aspirate was positive for adenovirus on a multiplex polymerase chain reaction (PCR) respiratory panel.Chest X-ray was unremarkable and blood-and urine cultures remained negative.Despite persistent fever, she was generally well and on the second day of admission her parents choose for an ambulatory follow-up.
Two days later she represented again in the emergency department because of high-grade fever, vomiting, and drowsiness.On admission, the girl was lethargic with symmetric but nonresponsive pupils, intermittent nystagmus, and eye deviation to the right.Te left tympanic membrane was erythematous and bulging.A computed tomography scan of the brain revealed a mild hydrocephalus with an acute otitis media and mastoiditis on the left side.Blood investigation showed a normal white blood cell count of 7.3 × 10 9 /L and highly elevated CRP of 319 mg/L.Te cerebrospinal fuid (CSF) obtained by lumbar puncture was purulent and revealed a leukocytosis of 345.000/μL (normal value: <5 leukocytes/μL), a low glucose value of less than 5 mg/dL (normal value: 40-80 mg/dL), and a high protein concentration of 1836 mg/dL (normal value: 5-40 mg/dL).Urgent treatment for bacterial meningitis was initiated with intravenous cefotaxime and dexamethasone.She was transferred to our university hospital for admission on the pediatric intensive care unit (PICU).
Shortly after admission at the PICU, further neurological deterioration was observed with increased drowsiness and decerebrate posturing of the right arm on pain stimuli.Furthermore, persistent eye deviation and hypertonia of the right arm and leg was noted and with the suspicion of convulsions treatment with levetiracetam was started.She was intubated and an urgent MRI of the brain revealed difuse meningitis accompanied by a subdural empyema over the right cerebral convexity and against the cerebral falx with additional signs of ventriculitis with hydrocephalus and periventricular edema.Te MRI also showed vascular involvement of the left cavernous sinus and the circle of Willis, which resulted in ischemic infarcts most notably in the left middle cerebral artery territory (Figures 1-3).Besides signs of left mastoiditis, contrast enhancement of the left os petrosum was noted.Te Gram stain of the liquor revealed Gram-negative bacilli (Figure 4) and multiplex PCR meningitis/encephalitis panel that targets 14 of the most common bacterial, viral, and fungal causes were negative.To cover for anaerobic and resistant Gram-negative organisms, therapy was switched to meropenem and initially also amikacin.CSF culture became positive one day later and F. necrophorum was identifed with matrix-assisted laser desorption/ionization time of fight (MALDI-TOF).Te antibiotic regimen was switched to ceftriaxone and metronidazole.Blood cultures remained negative.A lumbar puncture was repeated on day three and revealed a raised intracranial pressure of 25 cmH 2 O (normal value: <20 cm H 2 O) and still purulent CSF.An external ventricular drain in the right ventricle was placed and a left tympanocentesis with placement of a tympanostomy tube for source control was performed.Te CSF and purulent middle ear fuid cultures obtained during these procedures remained negative.Between day two and day four, after switching to antibiotics with strong efectivity against anaerobes, the patient remained afebrile and CRP decreased from 411 mg/L to 88 mg/L.However, on day fve, the fever recurred.CT of the brain showed increasing opacifcation of the left middle ear and mastoid, and a left mastoidectomy was performed.Despite only low doses of continuous midazolam in the frst 48 hours of admission, she remained comatose with roving eye movements, mid-dilated unresponsive pupils, absent tendon refexes, and asymmetric hypertonicity on the right side.Although patient-triggered breaths were noticed, she could not be weaned from the ventilator in the frst week after admission.On day 12, a new brain MRI showed a reduction of the difuse leptomeningeal enhancement, vessel wall enhancement, and cavernous sinus infammation.However, there was a slight increase of the subdural empyema, increase of ventriculitis, and a new ischemic infarction in the right globus pallidus.With these fndings, a collaborative decision was made with the team to restrict further surgical therapy (craniotomy for neurosurgical drainage of the subdural empyema) since a poor prognosis was to be expected.However, the neurological situation slightly improved in the end of the second week and extubation was successful on day 14.From day fve till 16, the patient remained afebrile and CRP gradually decreased to 15 mg/L.Te following weeks, the patient had intermittent low-grade fever with fuctuating CRP between 15 and 48 mg/L.MRI repeated on day 23 showed a slight decrease of the subdural empyema.Treatment with ceftriaxone and metronidazole was continued.Another MRI after 6.5 weeks treatment with intravenous ceftriaxone and metronidazole, showed a minimal right-sided residual empyema in the posterior fossa (Figure 5) and signs of petrous apicitis (mastoiditis of the apex of the os petrosum).Treatment was extended with another three weeks of oral doxycycline.Te patient was discharged from the hospital to a rehabilitation center on day 59.
Clinical neurological evaluation seven months after onset of the infection revealed a right central facial paresis and a severe central motor disorder type with right sided spasticdystonia hemiplegia and moderate psychomotor delay.

Discussion
F. necrophorum is an anaerobic Gram-negative rod-shaped bacterium: in total 35 species of Fusobacterium have been identifed.F. necrophorum is commonly present in the microbiome of the upper respiratory tract.Nevertheless, it 2 Case Reports in Pediatrics may cause local infections such as pharyngitis, tonsillitis, and otitis which can progress to more invasive infections such as mastoiditis, osteomyelitis, or septicemia.A complication of a F. necrophorum infection is Lemierre's syndrome in which a local infection in the oropharyngeal cavity is leading to septic thrombophlebitis with thrombosis in the internal jugular vein, followed by spread of septic emboli mostly to the lungs, liver, or joints [6].Meningitis is a rare complication.Table 1 provides an overview of all 39 previously published cases of F. necrophorum meningitis in children until the age of 18 years .Te pathogenic mechanism leading from F. necrophorum asymptomatic upper respiratory tract colonization to infection is not well defned.Studies have revealed a multifactorial pathogenesis including patientspecifc contributions by host, organism, and environmental factors [33].In Lemierre's syndrome, the primary infection spreads from the oropharyngeal mucosa into the lateral pharyngeal space and soft tissues of the neck, and two diferent pathogenic routes are proposed.Either direct invasion through the connective tissue and lymphatic or hematogenous spread [34].After the infection reaches the pharyngeal space and soft tissues, F. necrophorum can cause thrombosis in the smaller veins with extension to the internal jugular vein and sometimes retrograde extension to the sigmoid sinus.In meningitis, prolonged infammation and edema can lead to septic thrombophlebitis even with the release of emboli into the systemic circulation [35].Beside the classical Lemierre's syndrome, the otogenic variant of Lemierre's syndrome is also reported in children [23,36].In otogenic Lemierre's syndrome, a local infection spreads the mastoid through direct invasion or hematogenous spread to the cerebral venous sinus causing (septic) thrombophlebitis.Most cases of F. necrophorum meningitis occurred in previously healthy children.Jacobs et al. reported a history of a previous car accident without lesions [13] and Westhout et al. an aseptic meningitis [22], respectively, two months and two years before the meningitis making a causative relation less likely.In many patients, including ours, there is often no visible destruction of the bony wall of the middle ear, suggesting hematogenous spread of the infection to the meninges.Destruction of the bony wall of the middle ear in the cases with a mastoiditis is not reported.However, in our case, on the frst MRI of the brain contrast enhancement of the os petrosum was noticed, suggesting extensive infammation from the mastoid evolving to suppurative infammation of the petrous apex [37], which was noted on the third MRI.Tis petrous apicitis can occur if an infection of the middle ear and mastoid extends into the previously pneumatized petrous apex air cells.Te location of the petrous apex is the most medial of the os temporale and near important intracranial structures under which the cavernous sinus and the meninges.In our patient, there were signs of infammation of the cavernous sinus which suggests direct invasion from the mastoid and the os petrosum into the cavernous sinus and the meninges.
Children with F. necrophorum meningitis will mostly present with nonspecifc signs such as high-grade fever, headache, and neck stifness.Tese symptoms are the same as in any form of meningitis (bacterial or viral) and therefore no diferentiation can be made based on clinical presentation    Case Reports in Pediatrics only.However, the likelihood of a F. necrophorum meningitis increases if the clinical presentation is preceded by a recent upper respiratory tract infection, especially otitis media with purulent otorrhea, generally with minimal or no improvement on frst line antibiotics.Tis was also applicable in our case and recognition of this clinical feature in patients presenting with meningitis can be an argument for the early association of antibiotics covering anaerobic pathogens.Review of the literature revealed an age distribution with two peaks in incidence in children with F. necrophorum meningitis (Figure 6): the frst peak occurred in preschool children (mean age of 3 years and 10 months old, range 0.2-7 years) and a second peak in adolescents (mean age of 15 years old, range 12-17 years).Te primary infection in the younger children was otitis media or mastoiditis.Te primary infection in the adolescents seemed more diverse as sinusitis and a peritonsillar abscess were noted as primary infection too.Our data are supported by Yarden-Bilavsky et al. who respectively noted a median age of 2 years and 2 months and 1 year and 7 months in children with a mastoiditis caused by F. necrophorum [38,39].Our patient being three years old had an acute otitis media with mastoiditis.
F. necrophorum meningitis can be a challenging clinical diagnosis, complicated by the difculties in isolating and identifcation of the bacteria itself.Current pediatric infectious disease guidelines recommend only routinely aerobic blood cultures, and anaerobic blood cultures should only be obtained when clinically relevant [40,41].Moreover, smaller pediatric blood culture bottles are often used which support the growth of most common pathogens with a small blood volume but only intended for aerobic growth.
F. necrophorum only grows under strict anaerobic conditions.Furthermore, if anaerobic cultures are inoculated, the growth of F. necrophorum is often slow and sometimes the organisms fail to grow.Marcellus et al. reported a positive blood culture for F. necrophorum and the CSF stain showed Gram-negative bacilli, however the CSF culture remained negative [31].If growth succeeds, it often takes days before identifcation of F. necrophorum is possible; Jensen reported a median time of three to four days [42], while Hagelskjaer Kristensen and Prag reported a median time up to six days [43].In our patient, the diagnosis was suspected when the CSF revealed Gram-negative rods, with a defnitive identifcation of F. necrophorum one day later.Despite the clinical severity, blood cultures obtained before the start the antibiotics treatment remained negative.In 17 out of the 29 cases who reported the results of the specifc cultures, the diagnosis of a F. necrophorum meningitis was also confrmed by a positive CSF culture.In the 12 other cases, the diagnosis was confrmed by a positive blood culture in combination with clinical signs of meningitis and a positive CSF analysis with pleocytosis, high protein, and low glucose level.
Infants (outside the neonatal period) and children in suspicion of meningitis are often empirically treated with a third-generation cephalosporin (cefotaxime or ceftriaxone) with or without vancomycin [44,45].Tese antibiotics cover the most prevalent aerobic bacteria of meningitis in this age category, such as S. pneumoniae, H. infuenzae, and N. meningitidis.In our patient, cefotaxime was started and when the Gram stain of the CSF showed Gram-negative bacilli, therapy was switched to meropenem in suspicion of an anaerobic cause.One day later, F. necrophorum was identifed and treatment was amended to metronidazole and ceftriaxone.In the past decades, the antimicrobial resistance among anaerobes including F. necrophorum has increased making the susceptibility less predictable.Due to the production of beta-lactamase by some isolates, treatment with penicillin, ampicillin, amoxicillin and piperacillin are limited and beta-lactamase inhibitors such as clavulanate, sulbactam, or tazobactam should be added to the therapy [46].Other susceptible antibiotics for F. necrophorum are carbapenem, clindamycin, or metronidazole.However, in case of F. necrophorum meningitis, treatment with a beta-lactam beta-lactamase inhibitor is not sufcient because of the poor blood-brain barrier penetration of the beta-lactamase inhibitors.Metronidazole is a specifc anaerobic antibiotic with the advantages of a good blood-brain barrier penetration and oral availability and therefore a susceptible treatment in case of F. necrophorum meningitis [47].Since metronidazole only demonstrates anaerobic activity, the association of an antibiotic with aerobic efect remains necessary since polymicrobial infection might occur in anaerobic infections [46].In our review 23 authors reported the specifc antibiotic treatment.In four cases metronidazole was started as initial therapy, two of these patients had a full recovery and two recovered with morbidities.In 13 cases, metronidazole was added to the initial therapy, fve of these patients had full recovery, four recovered with morbidities, and three died.In six patients metronidazole was not used.As initial therapy in the latter, four of these patients started with cephalosporin/±amikacin, one patient with penicillin/ amikacin, and one with meropenem.Of these patients, fve died due to complications caused by the F. necrophorum meningitis.Almost all reported patients with F. necrophorum meningitis, including ours, underwent source control surgery, such as the placement of tympanostomy tubes, mastoidectomy, or endoscopic/surgical drainage of extra-or intracranial abscesses or empyema.Despite adequate treatment and early source control, the mortality and morbidity in children with a F. necrophorum meningitis remains high.Of the 27 patients, for which the authors reported the outcome, eight patients died and 11 patients, including our patient, recovered with morbidities.Chronical sequelae vary from mild neurological complications such as a moderate Horner syndrome to severe neurological impairment such as spastic hemiplegia.

Conclusion
Meningitis caused by F. necrophorum is a rare but serious infection which can occur in previously healthy children mostly preschool children and adolescents.As the clinical presentation and the laboratory fndings can be very similar to another meningitis caused by aerobic bacteria, a meningitis preceded by or associated with otitis media or mastoiditis should raise suspicion for F. necrophorum meningitis.Specifcally, when there is minimal or no improvement on empiric (often antiaerobic) antibiotic treatment.When a F. necrophorum meningitis is being suspected, it is important to obtain anaerobic cultures and to keep in mind that this pathogen can be difcult to culture.A negative culture does not rule out F. necrophorum meningitis.Prompt treatment with a third-generation cephalosporin and metronidazole are being recommended and surgical source control is often necessary.However, even with adequate treatment, the morbidity and mortality in children with F. necrophorum meningitis remains high.

Figure 1 :Figure 2 :
Figure 1: MRI day 1.Vessel wall imaging (axial 3D T1 TSE SPACE Dante) after IV gadolinium administration.(a) Tere is difuse supratentorial and infratentorial pathological leptomeningeal contrast enhancement compatible with meningitis.Also note the pathological contrast enhancement of the walls of the cerebral arteries, indicative of associated vasculitis.(b) Te cavernous sinus appears thickened on the left side and enhances more heterogeneously, suggestive of infammation.Tere is secondary narrowing of the left cavernous carotid artery.

Figure 3 :
Figure 3: MRI day 1.Axial maximum intensity projection (MIP) of the 3D time of fight MR angiography (3D TOF MRA) (a) and ADC map at the level of the basal ganglia (b).Te left internal carotid artery (long arrows) and proximal middle cerebral artery (short arrows) are narrowed on the 3D TOF MRA MIP reconstruction.Tere is a secondary ischemic infarct in the left basal ganglia, insular region, and temporal lobe, seen as low signal on the ADC map.

Figure 4 :
Figure 4: Gram stain of the cerebrospinal fuid with multiple Gram-negative bacilli clearly visible.

Figure 5 :
Figure 5: Follow-up MRI 18 months later.Vessel wall imaging (axial 3D T1 TSE SPACE Dante) after IV gadolinium administration.Te difuse leptomeningeal contrast enhancement and vessel wall contrast enhancement are no longer visible.Tere is limited residual contrast enhancement of the cerebellar tentorium (short arrow), and focal cystic encefalomalacia in the left mesial temporal lobe (long arrow) and basal ganglia (not shown) after ischemic infarction.

Figure 6 :
Figure 6: Distribution of age and primary infection site in children with F. necrophorum meningitis.

Table 1 :
Overview of all reported cases of F. necrophorum meningitis under the age of 18 years.